Skeletal development and bone healing in HIV-1 transgenic animal models

HIV;Transgenic rodent models;Bone microarchitecture;Bone biomechanics;Bone healing

Wang, Jason Lee ; Guldberg, Robert E. Mechanical Engineering Weitzmann, M. Neale Gleason, Rudolph L. Platt, Manu O. Temenoff, Johnna S. ; Guldberg, Robert E.

University:Georgia Institute of Technology

Department:Mechanical Engineering

关键词: HIV;    Transgenic rodent models;    Bone microarchitecture;    Bone biomechanics;    Bone healing;   

Others  :  https://smartech.gatech.edu/bitstream/1853/62245/1/WANG-DISSERTATION-2018.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

HIV and AIDS have drastically compromised the quality of life and lifespan for millions of people worldwide. The increasing effectiveness of and access to antiretroviral therapy has dramatically increased the life expectancy of those infected with HIV to nearly that of the general population. Once considered a death sentence, a positive HIV diagnosis with appropriate treatment is now a chronic condition bringing with it the premature onset of disorders traditionally associated with the natural aging process including cardiovascular disease, neurocognitive decline, kidney disease, and osteoporosis. It is well understood that HIV infection is a risk factor for osteopenia and osteoporosis and subsequently for fragility fractures. More recently, studies have established an increase in fracture prevalence in the HIV-infected population. However, the effects of HIV infection on bone are difficult to investigate in the clinical setting. Traditional risk factors for osteoporosis – such as vitamin D deficiency, drug use, smoking, and alcohol use – can complicate any observed effects that HIV may have. Despite the increased risk for fracture and fracture prevalence in the HIV-infected population, relatively few clinical studies and no pre-clinical studies have investigated the potential for HIV infection to adversely affect fracture healing. The main goal of this work was to investigate the effects of HIV on skeletal growth and bone healing as exhibited by HIV-1 transgenic rodent models, specifically the mouse and the rat. In addition to the extensive body of bone research conducted in mouse and rat models, the transgenic rodent models offer significant advantages for pre-clinical research over the more recognized non-human primate and humanized mouse models, including less time and expense. Additionally, HIV-1 transgenic rodent models have been used to study various comorbidities associated with HIV infection. Thus, we first characterized the skeletal phenotype in the HIV-1 transgenic mouse model by evaluating bone microarchitecture and biomechanics. We further assessed whether HIV mice present with impairment in long bone fracture healing. Second, we characterized the longitudinal skeletal changes in the growing HIV-1 transgenic rat. Finally, we investigated alterations to bone healing in the HIV-1 transgenic rat using a critically-sized segmental bone defect model. This work presents findings supporting an HIV associated skeletal phenotype that is exhibited by both HIV-1 transgenic mice and rats that reflects the clinical literature. Specifically, HIV animals have reduced cortical and trabecular bone mass and altered bone microarchitecture at multiple skeletal sites. These deleterious effects on bone structure resulted in decreased whole bone mechanics and may be age-dependent in HIV-1 transgenic rodents. More significantly, we present the first pre-clinical investigation into fracture healing in the HIV-1 transgenic rodents showing impaired bone healing in both HIV-1 transgenic mice and rats. Our findings support the clinical need to monitor skeletal health in the HIV infected population and further emphasize the unmet need for robust clinical studies to investigate bone healing in this growing and aging population.